scholarly journals Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10

2021 ◽  
Vol 22 (8) ◽  
pp. 4232
Author(s):  
Herman D. Lim ◽  
J. Robert Lane ◽  
Meritxell Canals ◽  
Martin J. Stone

Chemokines interact with chemokine receptors in a promiscuous network, such that each receptor can be activated by multiple chemokines. Moreover, different chemokines have been reported to preferentially activate different signalling pathways via the same receptor, a phenomenon known as biased agonism. The human CC chemokine receptors (CCRs) CCR4, CCR7 and CCR10 play important roles in T cell trafficking and have been reported to display biased agonism. To systematically characterize these effects, we analysed G protein- and β-arrestin-mediated signal transduction resulting from stimulation of these receptors by each of their cognate chemokine ligands within the same cellular background. Although the chemokines did not elicit ligand-biased agonism, the three receptors exhibited different arrays of signaling outcomes. Stimulation of CCR4 by either CC chemokine ligand 17 (CCL17) or CCL22 induced β-arrestin recruitment but not G protein-mediated signaling, suggesting that CCR4 has the potential to act as a scavenger receptor. At CCR7, both CCL19 and CCL21 stimulated G protein signaling and β-arrestin recruitment, with CCL19 consistently displaying higher potency. At CCR10, CCL27 and CCL28(4-108) stimulated both G protein signaling and β-arrestin recruitment, whereas CCL28(1-108) was inactive, suggesting that CCL28(4-108) is the biologically relevant form of this chemokine. These comparisons emphasize the intrinsic abilities of different receptors to couple with different downstream signaling pathways. Comparison of these results with previous studies indicates that differential agonism at these receptors may be highly dependent on the cellular context.

2011 ◽  
Vol 187 (5) ◽  
pp. 2067-2071 ◽  
Author(s):  
Deena L. Gibbons ◽  
Lucie Abeler-Dörner ◽  
Tim Raine ◽  
Il-Young Hwang ◽  
Anett Jandke ◽  
...  

2011 ◽  
Vol 286 (23) ◽  
pp. 20625-20636 ◽  
Author(s):  
Nicole Hajicek ◽  
Mutsuko Kukimoto-Niino ◽  
Chiemi Mishima-Tsumagari ◽  
Christina R. Chow ◽  
Mikako Shirouzu ◽  
...  

2020 ◽  
Author(s):  
Edward L. Stahl ◽  
Laura M. Bohn

AbstractIn a recent report by Gillis et al., 2020 (1), it was suggested that low intrinsic agonism, and not biased agonism, leads to an improvement in the separation of potency in opioid-induced respiratory suppression versus antinociception. Although the compounds that were tested have been shown to display G protein signaling bias in prior publications, the authors conclude that since they cannot detect biased agonism in their cellular signaling studies the compounds are therefore not biased agonists. Rather, they conclude that it is low intrinsic efficacy that leads to the therapeutic window improvement. Intrinsic efficacy is the extent to which an agonist can stimulate a G protein-coupled receptor (GPCR) response in a system. The designation of full agonist is made to compounds that produce the highest observable activation in a system (maximum intrinsic efficacy); agonists producing some fraction of that response are considered partial agonists. The maximum response window is determined by the cellular environment, receptor and effector expression levels, and the amplification readout of the system. Biased agonism takes into consideration not only intrinsic efficacy, but also potency (concentration required to reach half maximal efficacy) of an agonist in an assay. Herein, the data published in the aforementioned manuscript was used to rederive the intrinsic efficacy and bias factors as ΔΔlog(τ/KA) and ΔΔlog(Emax/EC50). Based on this reanalysis, the data does not support the conclusion that biased agonism, favoring G protein signaling, was not present. Further, these observations agree with prior studies wherein oliceridine, PZM21 and SR-17018 were first described as biased agonists with improvement in antinociception over respiratory suppression in mice. Therefore, introducing G protein signaling bias may be a means to improve opioid analgesia while avoiding certain undesirable side effects.


2018 ◽  
Vol 11 (542) ◽  
pp. eaar4309 ◽  
Author(s):  
Jo-Hao Ho ◽  
Edward L. Stahl ◽  
Cullen L. Schmid ◽  
Sarah M. Scarry ◽  
Jeffrey Aubé ◽  
...  

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1127-1134 ◽  
Author(s):  
Li V. Yang ◽  
Caius G. Radu ◽  
Li Wang ◽  
Mireille Riedinger ◽  
Owen N. Witte

Abstract G2A is a G-protein–coupled receptor (GPCR) involved in immune regulation. Previous studies have shown that lysophosphatidylcholine (LPC), a bioactive lipid associated with atherosclerosis and autoimmunity, acts through G2A to induce diverse biologic effects. Production of LPC during cell apoptosis serves as a chemotactic signal for macrophage recruitment. Here we demonstrate that macrophage chemotaxis to LPC is dependent on G2A function. Wild-type but not G2A-deficient mouse peritoneal macrophages migrated toward LPC. RNAi-mediated knockdown of G2A in J774A.1 macrophages abolished LPC-induced chemotaxis, whereas overexpression of G2A significantly enhanced this process. Mutation of the conserved DRY motif of G2A resulted in loss of chemotaxis to LPC, suggesting a requirement for G-protein signaling. Unlike most GPCRs, including the chemokine receptors, coupling to Gi is not required for LPC/G2A-mediated chemotaxis, but coupling to Gq/11 and G12/13 is necessary as judged by inhibition with dominant negative forms of these alpha subunits or with regulators of G-protein signaling (RGS) constructs. Collectively, these data establish that pertussis toxin–insensitive G2A signaling regulates macrophage chemotaxis to LPC. Defects in this signaling pathway may be related to the pathogenesis of systemic autoimmune disease.


Author(s):  
Nancy S. Krieger ◽  
David A. Bushinsky

Chronic metabolic acidosis stimulates cell-mediated net calcium efflux from bone mediated by increased osteoblastic cyclooxygenase 2 (COX2), leading to prostaglandin E2-induced stimulation of RANKL-induced osteoclastic bone resorption. The osteoblastic H+-sensing G-protein coupled receptor (GPCR), OGR1, is activated by acidosis and leads to increased bne resorption. As regulators of G protein signaling (RGS) proteins limit GPCR signaling, we tested whether RGS proteins themselves are regulated by metabolic acidosis. Primary osteoblasts were isolated from neonatal mouse calvariae and incubated in physiological neutral (NTL) or acidic (MET) medium. Cells were collected and RNA extracted for real time PCR analysis with mRNA levels normalized to RPL13a. RGS1, RGS2, RGS3, RGS4, RGS10, RGS11 or RGS18mRNA did not differ between MET and NTL; however by 30' MET decreased RGS16 which persisted for 60' and 3h. Incubation of osteoblasts with the OGR1 inhibitor CuCl2 inhibited the MET induced increase in RGS16 mRNA. Gallein, a specific inhibitor of Gβγ signaling, was used to determine if downstream signaling by the βγ subunit was critical for the response to acidosis. Gallein decreased net Ca efflux from calvariae and COX2 and RANKL gene expression from isolated osteoblasts. These results indicate that regulation of RGS16 plays an important role in modulating the response of the osteoblastic GPCR, OGR1, to metabolic acidosis and subsequent stimulation of osteoclastic bone resorption.


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